rs139779505

Positions:

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM1BP4_StrongBP6_Very_StrongBS2

The NM_000548.5(TSC2):c.5131G>A(p.Val1711Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000201 in 1,612,958 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00052 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00017 ( 1 hom. )

Consequence

TSC2
NM_000548.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12O:1

Conservation

PhyloP100: 2.68

Variant links:

Genes affected

TSC2 (HGNC:12363): (TSC complex subunit 2) This gene is a tumor suppressor gene that encodes the growth inhibitory protein tuberin. Tuberin interacts with hamartin to form the TSC protein complex which functions in the control of cell growth. This TSC protein complex negatively regulates mammalian target of rapamycin complex 1 (mTORC1) signaling which is a major regulator of anabolic cell growth. Mutations in this gene have been associated with tuberous sclerosis and lymphangioleiomyomatosis. [provided by RefSeq, May 2022]

TSC2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

PM1

In a domain Rap-GAP (size 227) in uniprot entity TSC2_HUMAN there are 284 pathogenic changes around while only 47 benign (86%) in NM_000548.5

BP4

Computational evidence support a benign effect (MetaRNN=0.06284088).

BP6

Variant 16-2088110-G-A is Benign according to our data. Variant chr16-2088110-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 64983.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2088110-G-A is described in Lovd as [Likely_benign]. Variant chr16-2088110-G-A is described in Lovd as [Pathogenic]. Variant chr16-2088110-G-A is described in Lovd as [Benign].

BS2

High AC in GnomAd4 at 79 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSC2	NM_000548.5 linkuse as main transcript	c.5131G>A	p.Val1711Met	missense_variant	40/42	ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9 linkuse as main transcript	c.5131G>A	p.Val1711Met	missense_variant	40/42	5	NM_000548.5	ENSP00000219476		P49815-1

Frequencies

GnomAD3 genomes

AF:

0.000519

AC:

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00159

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000620

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000240

AC:

AN:

250396

Hom.:

AF XY:

0.000243

AC XY:

AN XY:

135706

show subpopulations

Gnomad AFR exome

AF:

0.00142

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000621

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000133

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.000168

AC:

246

AN:

1460614

Hom.:

Cov.:

AF XY:

0.000179

AC XY:

130

AN XY:

726638

show subpopulations

Gnomad4 AFR exome

AF:

0.00131

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000441

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000127

Gnomad4 OTH exome

AF:

0.000331

GnomAD4 genome

AF:

0.000519

AC:

AN:

152344

Hom.:

Cov.:

AF XY:

0.000524

AC XY:

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.00159

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000621

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000119

Hom.:

Bravo

AF:

0.000555

ESP6500AA

AF:

0.000682

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000247

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 27, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 19, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 30, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 22, 2022	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2022	TSC2: BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 03, 2019	This variant is associated with the following publications: (PMID: 21984974, 22903760, 24631838, 27176796, 22558107, 28088512, 23514105) -

Tuberous sclerosis 2

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -

Hereditary cancer-predisposing syndrome

Benign:2

Benign, criteria provided, single submitter	curation	Sema4, Sema4	Jul 31, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 27, 2018	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Tuberous sclerosis syndrome

Other:1

not provided, no classification provided

curation

Tuberous sclerosis database (TSC2)

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.085

BayesDel_noAF

Uncertain

0.080

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.56

D;.;.;.;.;.;.;.;.;.;.;.;T;.;T

Eigen

Benign

0.15

Eigen_PC

Benign

0.13

FATHMM_MKL

Uncertain

0.82

LIST_S2

Uncertain

0.88

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.063

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

0.76

MutationAssessor

Benign

0.34

N;.;.;.;.;.;.;.;.;.;.;.;.;.;.

MutationTaster

Benign

0.97

D;D;D;D;D;D;D

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-0.16

N;.;.;N;.;N;.;.;N;N;.;.;.;.;N

REVEL

Uncertain

0.58

Sift

Uncertain

0.0070

D;.;.;D;.;D;.;.;D;D;.;.;.;.;D

Sift4G

Uncertain

0.017

D;.;.;D;.;D;.;.;D;D;.;.;.;.;D

Polyphen

1.0

D;.;.;.;D;D;.;.;D;D;.;.;.;.;.

Vest4

0.53

MVP

0.87

ClinPred

0.017

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.19

gMVP

0.50

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over